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2022 ELN recommendations for the management of AML in adults

Sep 28, 2022
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Learning objective: After reading this article, learners will be able to cite the latest European LeukemiaNet recommendations for the management of AML.

The AML Hub has previously covered the 2022 recommendations from the European LeukemiaNet (ELN) for the diagnosis of acute myeloid leukemia (AML). Here, we summarize the updated guidelines for the management of AML, from the same publication in Blood,1 by Döhner et al. on behalf of the ELN. This article includes a revised response criteria and treatment recommendations.

Response criteria and outcome measures

Alongside the categories outlined in the 2017 version of the recommendations, complete remission (CR) with partial hematologic recovery (CRh) has been introduced as a treatment response option for patients who meet all CR criteria but only have partial recovery of both neutrophils and platelets (Table 1).

Table 1. Treatment response criteria in AML*

Response category

Definition

CR

BM blasts <5%; absence of circulating blasts or blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1,000/μL); platelet count ≥100 × 109/L (100,000/μL)

CRh

ANC ≥0.5 × 109 (500/μL) and platelet count ≥50 × 109/L (50,000/μL), otherwise all other CR criteria met

CRi

All CR criteria except for residual neutropenia <1.0 × 109/L (1,000) or thrombocytopenia <100 × 109/L (100,000/μL)

MLFS

BM blasts <5%; absence of blasts with Auer rods; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery required

PR

All hematologic criteria of CR; decrease of BM blast percentage to 5–25%; and decrease of pre-treatment BM blast percentage by ≥50%

No response

Patients evaluable for response but who do not meet criteria for CR, CRh, CRi, MLFS, or PR are deemed as having no response prior to the response landmark. Patients who fail to achieve response by the designated landmark are designated as having refractory disease

Non-evaluable for response

Patients lack an adequate BM response evaluation, for instance due to early death, withdrawal prior to response assessment, or a technically suboptimal BM sample that precludes assessment

ANC, absolute neutrophil count; BM, bone marrow; CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; PR, partial remission.
*Adapted from Döhner, et al.

Furthermore:

  • Refractory disease is defined as no CR, CR with incomplete hematologic recovery (CRi), or CRh at the response landmark.
  • Relapsed disease is indicated by bone marrow (BM) blasts ≥5%, or the reappearance of blasts in the blood in ≥2 peripheral blood samples collected ≥1 week apart, or the development of extramedullary disease.
  • Minimal residual disease (MRD) relapse can be defined by the conversion from MRD negativity to MRD positivity, or by an increase of MRD copy number ≥1 log10 between any two positive samples in patients with no CR, CRi, or CRh at the response landmark with MRD detection at low-level.
  • It is recommended to report early death, for example at 30 and 60 days, to enable recording of treatment-related mortality (TRM).
  • Event-free survival (EFS) and relapse-free survival (RFS) can be used as alternative endpoints to overall survival (OS), and the definition has been broadened to include CRh, CRi, and MRD outcomes:
    • EFSMRD is measured from Day 1 of randomization (or Day 1 of registration in non-randomized trials) to the date of failure to achieve CR, CRh or CRi by a defined landmark, hematologic relapse, MRD relapse, or death from any cause.
    • RFSMRD is measured from the date of achievement of remission until the date of hematologic relapse, MRD relapse, or death from any cause
    • Cumulative incidence of relapse (CIRMRD) is measured from the date of achievement of remission until the date of hematologic relapse, or MRD relapse. Patients who died without relapsing are counted as a competing cause of failure.
    • Cumulative incidence of death (CIDMRD) is measured from the date of achievement of remission to death without prior relapse; relapse is considered as a competing risk.
  • Within clinical trials, patients not achieving a response by or dying before the pre-determined landmark should have the event recorded on Day 1; alive but unevaluable patients should be censored on Day 1.

Therapeutic options

  • Genetic analysis results should be made available as soon as possible, preferably within 3–5 days.
  • Time should be taken before starting therapy allowing patients to be stabilized, and the most appropriate best treatment to be identified.
  • The same therapeutic principles should be applied regardless of whether a patient is eligible for intensive therapy or if it is deemed that non-intensive therapy is more suitable.
    • If a patient cannot tolerate an active intensive or non-intensive treatment option with the aim of control and/or eradication of disease, the purpose of therapy should be to optimize quality of life and decrease the incidence of cytopenia-related complications with supportive care measures and early involvement of palliative care services as appropriate.

Fit patients

  • Anthracyclines and cytarabine remain the primary induction options for intensive chemotherapy, with the multiagent regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) and mitoxantrone-based cytarabine regimens as alternatives. Midostaurin is recommended to be incorporated in treatment regimens for patients with FLT3-mutated AML.
  • Consolidation therapy should include intermediate-dose cytarabine when possible. In patients who have achieved CR, MRD assessment is helpful to inform consolidation treatment choice.
  • Patients treated with midostaurin during induction and as consolidation therapy may continue it as maintenance.

Unfit patients

  • In the absence of criteria to determine whether a patient is ineligible for intensive chemotherapy, criteria used in clinical trials may be of use in routine practice.
  • Venetoclax or decitabine plus azacitidine is the new standard of care for patients unfit for intensive chemotherapy.
  • Venetoclax plus low-dose cytarabine is an alternative for patients who cannot receive a hypomethylating agent.
  • Rapid screening for IDH1 mutation at diagnosis is recommended to identify patients suitable for treatment with ivosidenib.
  • Due to high incidences of early responses found with hypomethylating agent (HMA) combinations, patients receiving HMA combination should be evaluated for early response during the first cycle (Days 14–21). Early assessment can also inform dose management, such as changing or delaying doses in the event of persistent cytopenias in a leukemia-free BM.

Management of adverse events

Patients should be monitored closely to manage adverse events, particularly to novel therapeutics. The ELN recommendations for the management of adverse effects of novel agents are displayed in Table 2.

Table 2. Management of selected adverse events for novel agents*

Agent

AE requiring special attention

Recommended management

FLT3 inhibitors

               Midostaurin

QT prolongation

Dose interruption/reduction, substitution of QT prolonging co-medication if possible, otherwise additional ECG controls

               Gilteritinib

Transaminase elevation

If Grade ≥3, dose interruption/reduction

QT prolongation

Dose interruption/reduction, substitution of QT prolonging co-medication

PRES

Discontinuation

IDH inhibitors

               Ivosidenib

Differentiation syndrome

Dex, hydroxyurea for co-occurring leukocytosis, dose interruption/reduction

QT prolongation

Dose interruption/reduction, substitution of QT prolonging co-medication

               Enasidenib

Differentiation syndrome

Dex, hydroxyurea for co-occurring leukocytosis, dose interruption/reduction

Bilirubin elevation

Dose interruption/reduction

Conjugated antibodies

               Gemtuzumab
               ozogamicin
 

Transaminase elevation

Bilirubin elevation

Dose interruption/reduction

VOD/SOS

Dose interruption, supportive care, fluid management, possibly defibrotide

BCL-2 inhibitors

               Venetoclax

Neutropenia

Thrombocytopenia

Early response assessment (Day 14–21 of Cycle 1), if BM blasts <5%, cease Ven for up to 14 days to allow count recovery to ≥ CRh. If neutropenia does not recover within 7 days of ceasing Ven, add in G-CSF

Subsequent cycles: Aza 75 mg/m2 SC/IV Day 1–7 (or Day 1–5 + Day 8–9) or Dec 20 mg/m2 IV Day 1–5 plus Ven 400 mg OD, or LDC 20 mg/m2 SC Day 1–10 plus Ven 600 mg OD q4 weeks until progression

Delayed count recovery or recurrent treatment-emergent Grade 4 neutropenia/thrombocytopenia lasting ≥7 days require reductions in the duration of Ven (from 28 to 21 or 14 days, or less) and/or reductions in Aza, Dec, or LDC dose if severe BM hypoplasia

Tumor lysis syndrome

Dose ramp-up in Cycle 1; hydration, prophylaxis with uric acid lowering drugs, electrolyte monitoring, and reduction of WBC to <25 × 109/L

Interaction with CYP3A inhibitors

Moderate CYP3A inhibitors, reduce Ven dose by ≥50%; ramp-up phase: 50 mg on Day 1, 100 mg on Day 2, 200 mg PO OD from Day 3

Strong CYP3A inhibitors, ramp-up phase: 10 mg on Day 1, 20 mg on Day 2, 50 mg on Day 3, 100 mg (or less) OD PO from Day 4

Hedgehog pathway inhibitors

               Glasdegib

Muscle spasms

Dose interruption/reduction

QT prolongation

Dose interruption/reduction, substitution of QT prolonging comedication if possible

Chemotherapy

               CPX-351

Prolonged myelosuppression

Anti-infectious prophylaxis

Hypomethylating agents

               CC-486/oral
               azacitidine
 

Neutropenia, thrombocytopenia

Dose interruption/reduction, myeloid growth factors

Nausea, vomiting, diarrhea

Prophylactic anti-emetics

AE, adverse events; Aza, azacitidine; BM, bone marrow; CRh, complete remission with partial hematologic recovery; D, day; Dec, decitabine; Dex, dexamethasone; ECG, electrocardiogram; G-CSF, granulocyte colony-stimulating factor; IV, intravenous; LDC, low-dose cytarabine; OD, once daily; PO, per oral administration; PRES, posterior reversible encephalopathy syndrome; q4, every four; SC, subcutaneous; SOS, sinusoidal obstructive syndrome; Ven, venetoclax; VOD, veno-occlusive disease; WBC, white blood cell count.
*Adapted from Döhner, et al.

Relapsed/refractory AML

  • Molecular re-evaluation is important at relapse in order to identify potential targets for targeted salvage therapies.
  • Patients should be entered into clinical trials where possible.
  • Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended if cytoreduction is achieved; non-intensive options for disease control, such as hypomethylating agents, are recommended if allo-HSCT is not an option.

Allo-HSCT

  • Cytogenetic and molecular genetic features of disease, response to initial treatment, and patient, donor, and transplant factors should be taken into account when determining the risks and benefits of allo-HSCT.
  • Allo-HSCT should be considered if there is a relapse probability of >35–40% without it.
  • Allo-HSCT is not recommended for patients with favorable-risk disease in first CR unless there is inadequate MRD clearance but is recommended for patients with intermediate-risk and high-risk disease, depending on MRD status. Patients >60 years should be carefully selected for allo-HSCT, taking into account any co-morbidities.
  • Where possible, sibling donor or well-matched unrelated donors are the preferred option for adults with AML; the use of relatives with deleterious germline variants should be avoided.
  • For patients relapsing post-allo-HSCT with FLT3-mutated AML, gilteritinib is the preferred treatment option.

Clinical trials

  • Patients with AML should be enrolled in a suitable clinical trial whenever possible, with real-time rapid-biomarker screening available to enable enrollment into trials of defined subpopulations.
  • To maximize future research, biobanking should be standard practice for all clinical trials.

Special situations

  • Patients with hyperleukocytosis (white blood cell count >100 × 109/L) and those receiving venetoclax should be observed for tumor lysis syndrome.
  • Patients receiving treatment with isocitrate dehydrogenase inhibitors should be closely monitored for signs of differentiation syndrome.

Supportive care

  • A vaccination strategy for influenza and COVID-19 is recommended for all patients with AML.
  • Consider antifungal prophylaxis with posaconazole during remission induction therapy.
  • If regular blood counts are not possible, platelet and hemoglobin thresholds necessitating transfusion should be increased.
  • The assessment of bleeding risk should include platelet count, mucosal bleeding, infection, severe mucositis, and fever; these factors indicate a need for an increased platelet level transfusion threshold.
  • It is recommended to aim for hemoglobin levels of >8 g/dL, with a platelet count of <10 × 109/L suggesting platelet transfusions are required.

Conclusion

Recent improvements in technologies and therapies for the management and treatment of patients with AML, and the influence these advancements have had on the standard of care and clinical trials, have informed the 2022 ELN recommendations.

  1. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. 2022;140 (12):1345-1377. DOI:10.1182/blood.2022016867